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A number of new studies on ovarian cancer show “promising” results for patients who develop chemo-resistance

A Dutch study uses conventional chemotherapeutics more intensively

Another study uses a new class of drug discovered by the UK’s Institute of Cancer Research

Genetic testing is playing an increasing role in the reduction of chemo-resistance

Since 2014 the Royal Marsden NHS Trust Hospital in London has employed genetic profiling of ovarian cancer patients

The UK’s Chief Medical Officer suggests that whole genome sequencing should become standard practice on the NHS across cancer care

A new class of chemotherapeutic agent is directed at targeting cancers with defective DNA-damage repair

Improvements in cancer care have been both scientific and organizational

Utilizing and sequencing the treatment options for ovarian cancer may have a significant impact on the overall survival rates of patients

Multidisciplinary teams are transforming ovarian cancer care

Improving ovarian cancer treatment

Part II

Part-1 described ovarian cancer, the difficulties of diagnosing the disease early, and the challenges of developing effective screening mechanisms for it in pre-symptomatic women. Here, in part-2, we report new studies, which hold out the prospect of improved treatment options for women living with ovarian cancer. Both Commentaries draw on some of the world’s most eminent ovarian cancer clinicians and scientists.

1

Established chemotherapy agents combined and used intensively

The first study we describe is Dutch, published in 2017 in the British Journal of Cancer. It reports findings of a pioneering type of intensive chemotherapy, which was effective in 80% of patients with advanced ovarian cancer and whose first line of chemotherapy had failed. Currently, such patients have few options because more than 50% do not respond to follow-up chemotherapy.

Intensive combinations

The study, led by Dr. Ronald de Wit, of the Rotterdam Cancer Institute, involved 98 patients who first responded to chemotherapy only later to relapse. Patients in the study were divided into three groups according to the severity of their condition, and treated with a combination of two well established chemotherapy agents: cisplatin and etopside, but the new treatment used the drugs much more intensively than usual.

Usually, chemotherapy is delivered as a course of a number of 21-day sessions (cycles) over several months. Between cycles patients are given time to recover from the toxic side effects, including neurotoxicity, nephrotoxicity, ototoxicity, and chemotherapy-induced nausea and vomiting (CINV). In de Wit’s study the combined chemotherapy drugs were given intensively, on a weekly basis, along with drugs to prevent adverse side effects.

Findings

Among the group of women in de Wit’s study who were most seriously ill, 46% responded to the new treatment, compared with less than 15% for current therapies. The response rates of the two groups of women who were least ill to the new treatment were 92% and 91%. This compares to responses of 50% and 20 to 30% with standard therapies. Overall, 80% of the women's tumours shrank, and 43% showed a complete response, with all signs of their cancers disappearing.

Immediate benefit

"We were delighted by the success of the study. The new drug combination was highly effective at keeping women alive for longer, giving real hope to those who would otherwise have had very little . . . . We were worried the women would be too ill to cope with the treatment, but in fact, they suffered relatively few side effects. And since these drugs are readily available, there's no reason why women shouldn't start to benefit from them right away," says de Wit.

2

ONX-0801 study

The second study we report was presented at the 2017 American Society of Clinical Oncology (ASCO) meeting in Chicago. It describes findings of an experimental new treatment that was found to dramatically shrink advanced ovarian cancer tumors, which researchers suggest is, “much more than anything that has been achieved in the last 10 years”.

“Very promising” findings

Dr. Udai Banerji, the leader of the study, is the Deputy Director of Drug Development at the UK’s Institute of Cancer Research (ICR). Banerji and his team were testing a drug, known as ONX-0801, for safety, but found that tumors, in half of the 15 women studied, shrank during the trial. A response Banerji called, “highly unusual”, and “very promising”. The drug, which is, “a completely new mechanism of action,” could add, “upward of six months to the lives of patients with minimal side effects”. If further clinical studies prove the drug’s effectiveness, it could potentially be used in early-stage ovarian cancer where, “the impact on survival may be better,” says Banerji.

New class of drug

ONX-0801 is the first in a new class of drug discovered by the ICR, and tested with the Royal Marsden NHS Foundation Trust. It attacks ovarian cancer by mimicking folic acid in order to enter the cancer cells. The drug then kills these cells by blocking a molecule called thymidylate synthase. ONX-0801 could be effective in treating the large group of chemo-resistant sufferers for whom there are currently limited options. Additionally, because the new therapy targets cancer cells and does not affect surrounding healthy cells, there are fewer side effects. Further, experts have developed tests to detect the cells that respond positively to this new treatment, which means oncologists can identify those women who are likely to benefit from the therapy the most.

Cautious note

Although the study is said to be “very promising”, Michel Coleman, Professor of Epidemiology at the London School of Hygiene & Tropical Medicine, suggests caution in interpreting its findings as it is such a small study and while, “shrinkage of tumors is important . . . it is not the same as producing the hoped-for extension of survival for women with ovarian cancer.”

3

Genetic testing

Resistance to chemotherapy can be reduced by DNA testing to obtain an increased knowledge of the molecular mechanisms of ovarian cancer pathogenesis, which facilitate personalized therapies that target certain subtypes of the disease. “Some people choose to have DNA testing because either they have developed cancer or family members have,” says David Bowtell, Professor and Head of the Cancer Genomics and Genetics Program at Peter MacCallum Cancer Centre, Melbourne, Australia. “In the context of cancer, personalized medicine is the concept that we look into the cancer cell and understand for that person what specific genetic changes have occurred in their cancer. Based on those specific changes, for that person we then decide on a type of therapy, which is most appropriate for the genetic changes that have occurred in that cancer . . . . . Typically this involves taking a sample of the cancer, running it through DNA sequencing machines, and using bioinformatics to interpret the information. Then, the results, which include gene mutations need to be interpreted by a multidisciplinary team, in order to decide the best possible treatment options for that particular patient,” says Bowtell: see videos below..

How do genetic mutations translate into personalised medicine?

How is personalised medicine implemented?

Mainstreaming cancer geneticsSince 2014 the Royal Marsden NHS Trust Hospital in Londonhas employed genetic profiling of ovarian cancer patients, and have used laboratories with enhanced genetic testing capabilities to streamline and speed up processing time, lower costs, and help meet the large and growing demand for rapid, accurate and affordable genetic testing. The program called, Mainstreaming Cancer Genetics, helps women cancer patients make critical decisions about their treatment options. Currently, fewer than 33% of patients are tested, but this study spearheaded the beginning of a significant change. In her 2017 Annual Report, Professor Dame Sally Davies, England’s Chief Medical Office suggested that within the next 5 years all cancer patients should be routinely offered DNA tests on the NHS to help them select the best personalized treatments.

Bringing genetic testing to patientsAccording to Nazneen Rahman, Professor and Head of the Division of Genetics and Epidemiology at the ICR, and Head of the Cancer Genetics Unit at the Royal Marsden Hospital, London, “There were two main problems with the traditional system for gene testing. Firstly, gene testing was slow and expensive, and secondly the process for accessing gene testing was slow and complex . . . . We used new DNA sequencing technology to make a fast, accurate, affordable cancer gene test, which is now used across the UK. We then simplified test eligibility and brought testing to patients in the cancer clinic, rather than making them have another appointment, often in another hospital.”

More people benefiting from affordable rapid advanced genetic testingTreatment strategies that improve the selectivity of current chemotherapy have the potential to make a dramatic impact on ovarian cancer patient outcomes. The Marsden is now offering genetic tests to three times more cancer patients a year than before the program started. The new pathway is faster, with results arriving within 4 weeks, as opposed to the previous 20-week waiting period. According to Rahman, “Many other centres across the country and internationally are adopting our mainstream gene testing approach. This will help many women with cancer and will prevent cancers in their relatives.” If the UK government acts on the recommendations of Davies, there could be a national center for genetic testing within the next 5 years.

4

PARP Inhibitors and personalized therapy

Since 2 seminal 2005 publications in Nature, (Bryant et al, 2005; and Farmer et al, 2005) which reported the extremely high sensitivity of BRCA mutant cell lines to the enzyme poly (ADP-ribose) polymerase (PARP) inhibition, there has been a scientific race to exploit a new class of cancer drug called PARP inhibitors. The family of PARP inhibitors represents a widely researched and promising alternative for the targeted therapy of ovarian malignancies. Over the past few years, PARP inhibitors have successfully moved into clinical practice, and are now used to help improve progression-free survival in women with recurrent platinum-sensitive ovarian cancer.Recent (PARP) approvalsIn 2014, olaparib was the first PARP inhibitor to obtain EU approval as a treatment for ovarian cancer patients who had become resistant to platinum-based chemotherapy. In 2017, the FDA granted the drug ‘priority review’ as a maintenance therapy in relapsed patients with platinum-sensitive ovarian cancer while confirmatory studies are completed. In December 2016, the FDA granted ‘accelerated approval’ for rucaparib, another (PARP) inhibitor for the treatment of women with advanced ovarian cancers who have been treated with two or more chemotherapies, and whose tumors have specific BRCA gene mutations.

Early in 2017, the drug niraparib was the first PARP inhibitor to be approved by the FDA for the maintenance treatment of adult patients with recurrent gynaecological cancers who are resistant to platinum-based chemotherapy. The approval was based upon data from an international randomized, prospectively designed phase III clinical study, which enrolled 553 patients, and showed a clinically meaningful increase in progression-free survival (PFS) in women with recurrent ovarian cancer, regardless of BRCA mutation or biomarker status. In conjunction with the accelerated 2017 FDA approval for rucaparib, the FDA also approved a BRCA diagnostic test, which identifies patients with advanced ovarian cancer eligible for treatment with rucaparib.

New class of chemotherapiesPARP inhibitors may represent a potentially significant new class of chemotherapeutic agents directed at targeting cancers with defective DNA-damage repair. Currently, these drugs have a palliative indication for a relatively small cohort of patients. In order to widen the prospective patient population that would benefit from PARP inhibitors, predictive biomarkers based on a clearer understanding of the mechanism of action, and a better understanding of their toxicity profile will be required. Once this is achieved PARP inhibitors could to be employed in the curative, rather than the palliative setting.

5

The future of cancer care and multidisciplinary teams

According to Hani Gabra, Professor of Medical Oncology at Imperial College, London; and Head of AstraZeneca’s Oncology Discovery Unit, we now have “many options” for treating ovarian cancer. However, “how we utilize and sequence these options may have a significant impact on the overall survival of a patient. Better understanding of the disease through science is constantly turning up new options. For the first time in the last 5 years we are developing options in real time for patients. Patients almost are able to benefit from these options as they are relapsing from their disease. Keeping patients alive for longer allows them to access new treatments . . . It’s truly remarkable to see this in real time as a doctor,” says Gabra: see video.

A significant number of mostly private patients diagnosed with ovarian cancer draw comfort from the belief that they, “have the best oncologist”. This view fails to grasp the challenges facing individual clinicians acting on their own to treat a devilishly complex disease such as ovarian cancer. “The main improvements in cancer care have been organizational and scientific.” says Gabra. “It is not enough to create new science and new treatments. It is also important to rigorously implement these. The most effective way to do this is via a ‘tumor board’ or a ‘multidisciplinary clinic or team’, where various specialists such as surgeons, radiotherapists, medical oncologists, pathologists, clinical nurse specialists, etc come together and discuss each individual patient. Such multidisciplinary discussion results in the best utilizations of currently available treatment options in the right sequence. It’s difficult to do this for a doctor acting on his or her own and making isolated decisions . . . Multidisciplinary decision-making has transformed cancer care,” says Gabra: see video.

Takeaways

This Commentary provides a flavor of some of the recent advances in ovarian cancer research and care, and suggests that treatment options have improved in the 4 years since Maurice Saatchi described ovarian cancer care as, “degrading, medieval and ineffective” leading “only to death”. However, it is worth stressing that care is both organizational and scientific, and multidisciplinary teams can transform care and prolong life.